Carl C. Hug

Intravenous fentanyl kinetics

Fentanyl is considered to be a short‐acting narcotic analgesic but prolonged and recurrent ventilatory depression has been reported. We examined fentanyl kinetics and excretion in 7 healthy male subjects who were given a 3.2‐ or 6.4‐μg/kg dose of 3H‐fentanyi intravenously. Arterial blood and urine samples were analyzed for unchanged fentanyl and total radioactivity. Fentanyl concentrations fell rapidly and 98.6% of the dose was eliminated from plasma in 60 min but the terminal elimination phase of fentanyl from the body was slow (t½β = 219 min) due to the slow return of the unchanged drug from a peripheral compartment to the central compartment where elimination occurred primarily by biotransformation. Eighty‐five percent of the dose was recovered in urine and feces in 72 hr; less than 8% was recovered as unchanged fentanyl. There were fluctuations in plasma fentanyl levels during the elimination phase in all cases. The long t½β and fluctuations in plasma levels may contribute to prolonged and recurrent ventilatory effects of fentanyl.

Pharmacokinetics of Remifentanil (GI87084B) and Its Major Metabolite (GI90291) in Patients Undergoing Elective Inpatient Surgery

BackgroundRemifentanil is a highly potent opioid with a rapid onset and a short duration of action due to its rapid hydrolysis by esterases in blood and tissues. The major metabolite of remifentanil, GI90291, is much less potent than remifentanil. MethodsThe pharmacokinetics of remifentanil and its major metabolite, GI90291, were determined in 24 patients undergoing elective inpatient surgery. Remifentanil was administered as a 1-min infusion (2, 5, 15, and 30 μg/kg) after the induction of anesthesia and tracheal intubation. Serial arterial blood samples were collected over 6 h and assayed for remifentanil and GI90291. ResultsThe pharmacokinetics of remifentanil were described using a three-compartment model. Total clearance (250–300 1/h) of remifentanil was independent of dose and was approximately three to four times greater than the normal hepatic blood flow. Volume of distribution at steady state (25–40 1) also was independent of dose. The terminal half-life of remifentanil ranged from 10 to 21 min. Covariate analysis of remifentanil clearance and patient demographics showed that patient body weight, age, and gender did not influence total clearance. This suggests that remifentanil may not need to be dosed according to body weight in adult patients. A simulation was conducted to determine the time required for a 50% reduction in effect site concentration after an infusion designed to maintain a constant effect site concentration. The time required for a 50% reduction in the effect site concentration of remifentanil (3.65 min) was considerably less than that for sufentanil (33.9 min), alfentanil (58.5 min), and fentanyl (262 min). The pharmacokinetics of the major metabolite, GI90291, were independent of the dose of remifentanil. The mean terminal half-life of GI90291 ranged from 88 to 137 min. ConclusionsThe pharmacokinetics of remifentanil are consistent with its rapid elimination by blood and tissue esterases; its major metabolite is eliminated more slowly but is not likely to make any significant contribution to the total effect because of its much lower potency. The rapid onset and short duration of action of remifentanil make it well suited for titration of dose (infusion rate) to the desired degree of effect.

Plasma Concentrations of Alfentanil Required to Supplement Nitrous Oxide Anesthesia for General Surgery

To design an efficient infusion regimen from pharmacokinetic data, it is necessary to know the alfentanil plasma concentrations required for satisfactory anesthesia. In 37 patients about to undergo lower abdominal gynecologic, upper abdominal, or breast surgery, anesthesia was induced with alfentanil 150 μg/kg iv and 66% N2O in oxygen. Thereafter, N2O anesthesia was supplemented with a continuous infusion of alfentanil that was varied between 25 and 150 μg · kg-1 · h-1, as indicated by the patients responses to surgical stimulation. Small bolus doses of alfentanil 7 or 14 μg/kg were administered and the infusion rate increased to suppress precisely defined somatic, autonomic, and hemodynamic responses. Arterial plasma concentrations of alfentanil were measured during the operation when the patient did and did not respond to noxious stimulation. Logistic regression was used to determine plasma concentration–effect curves for different stimuli. Plasma alfentanil concentrations required along with 66% N2O to obtund responses to single episodes of stimulation in 50% of the 37 patients (Cp50 ± SE) were: 475 ± 28 ng/ml for tracheal intubation, 279 ± 20 ng/ml for skin incision, and 150 ± 23 ng/ml for skin closure. Between skin incision and closure, multiple determinations of response/no response were made for each patient and an individual Cp50 was estimated. The Cp50 (mean ± SD) for the three surgical procedures were: breast, 270 ± 63 ng/ml (n = 12); lower abdominal, 309 ± 44 ng/ml (n = 14); and upper abdominal, 412 ± 135 ng/ml (n = 11). The Cp50 for satisfactory spontaneous ventilation after the discontinuation of N2O was 223 ± 13 ng/ml. These data demonstrate that different perioperative stimuli require different alfentanil concentrations to suppress undesirable responses. Thus, the alfentanil infusion rate should be varied according to the patients responsiveness to stimulation in order to maintain satisfactory anesthetic and operative conditions and to provide rapid recovery of consciousness and spontaneous ventilation.

The Anesthetic Potency of Fentanyl in Terms of Its Reduction of Enflurane MAC

Infusion rates for fentanyl were calculated to produce stable plasma concentrations at which the ability of fentanyl to reduce enflurane MAC could be studied utilizing the tail clamp method and measurement of end-tidal enflurane. Following the determination of control enflurane MAC in each animal, an infusion of fentanyl was begun. Group 1 received continuous successive infusion rates of 0.05, 0.1, and 0.2 μg · kg−1 · min−1 with respective loading doses (given over 20 min) of 15, 15, and 30 μg/kg; Group 2 received infusions of 0.2, 0.8, and 3.2 μg · kg−1 · min −1 with loading doses of 30, 90, and 270 μg/kg, respectively. Group 3 was studied in the same manner except that fentanyl was omitted from the infusion solution. Enflurane MAC was determined at each infusion level and blood samples were analyzed for the concentration of fentanyl. Fentanyl concentrations in plasma were proportional to the infusion rate. Enflurane MAC was decreased significantly in proportion to fentanyl plasma concentrations up to 30 ng/ml where a reduction of MAC by 65% was evident. A threefold higher concentration produced a minimal further reduction. In Group 3 dogs, no change in enflurane MAC was seen. It was concluded that predictable, stable levels of fentanyl in plasma can be achieved, that there is a close relationship between the concentration of fentanyl in plasma and its enflurane sparing effect, and that there is a ceiling to this concentration-response relationship.

Histamine concentrations and hemodynamic responses after remifentamil

Remifentanil is a new potent opioid analgesic that undergoes rapid esterase metabolism.The purpose of this study was to investigate hemodynamic responses to 2-30 micro gram/kg remifentanil (escalating doses) injected as a bolus over 1 min during general anesthesia. After general anesthesia with endotracheal intubation, placement of a radial artery catheter, and pretreatment with glycopyrrolate, remifentanil 2, 5, 15, or 30 micro gram/kg (six patients, three male and three female per group) was administered over 1 min. Arterial blood pressure and heart rate were measured noninvasively before drug administration, after drug administration, and then every minute for 5 min. Arterial blood was taken for histamine determinations before drug administration and then at 1, 3, and 5 min after drug administration. Administration of remifentanil was associated with a reduction in systolic blood pressure from 134 +/- 18 to 91 +/- 16 mm Hg and heart rate from 99 +/- 20 to 69 +/- 21 bpm and was not associated with alterations in histamine concentration. (Anesth Analg 1995;80:990-3)

The pharmacokinetics of remifentanil

Opioids decrease the sympathetic and somatic responses to noxious stimulation and can be given in high doses without negative inotropic effects, even in patients with impaired cardiac function. With currently available opioids, precise titration of dose to effect is difficult, and high doses result in drug accumulation and prolonged respiratory depression. Remifentanil is a new synthetic opioid with direct action on mu-opioid receptors. It has a rapid onset and short latency to peak effect. It is rapidly inactivated by esterases in both blood and tissues, resulting in a very short duration of action. The context-sensitive half-life remains very short (3 to 4 minutes), independent of the duration of infusion. These characteristics facilitate titration of dose to effect and also allow the use of very high doses (ED99) without prolonging recovery from its effects. The duration of action of remifentanil has been found to be short, even in patients with renal or hepatic failure, although only low doses have been used in the studies published to date. The hydrolysis of remifentanil produces a metabolite with very weak opioid receptor activity that does not contribute to the effects of remifentanil. Possible disadvantages of the drug include (1) the need to mix the lyophilized drug with a diluent, (2) administration as a continuous infusion, (3) risk of rapid loss of analgesic and anesthetic effects if the infusion is interrupted accidentally, and (4) difficulty in judging the dose of another, longer lasting opioid that will be required to control postoperative pain without producing excessive ventilatory depression. Remifentanil is likely to be more expensive than other opioids, but its use may reduce overall costs if prompt recovery from its effects results in shorter stays in the operating room and recovery units.

The enflurane sparing effect of morphine, butorphanol, and nalbuphine.

The potencies of morphine and of the narcotic analgesic agonistantagonists butorphanol and nalbuphine in terms of their ability to decrease enflurane MAC were studied. Following the determination of control MAC for enflurane in each dog, an intravenous bolus dose of either butorphanol tartrate, nalbuphine hydrochloride, morphine, or placebo was administered and enflurane MAC was redetermined. A higher dose of the same drug was then administered and enflurane MAC was redetermined up to a total of four doses in each animal. The successive doses for morphine and nalbuphine were 0.5, 1.5, 5.0, and 20.0 mg/kg; for butorphanol, 0.1, 0.3, 1.0, and 4.0 mg/kg; lactated Ringers solution was used as a placebo. Both butorphanol and nalbuphine produced significant reductions of enflurane MAC (11 and 8%, respectively) at their lowest doses. No further reductions were produced by three- to fortyfold larger doses of either agonist-antagonist. Morphine produced a 17% reduction of enflurane MAC at the lowest dose with progressive decreases of enflurane MAC up to 63% at a dose of 5 mg/ kg morphine. A fourfold increase in the morphine dose did not further decrease MAC. No change in enflurane MAC occurred in the animals given placebo. It was concluded that there is a “ceiling” to the potency of butorphanol and nalbuphine as anesthetic supplements. There is also a limit to the anesthetic sparing effect of morphine, but it is considerably greater than that of the agonistantagonist narcotic analgesic.

Hemodynamic Changes during Fentanyl—Oxygen Anesthesia for Aortocoronary Bypass Operation

Fentanyl in doses of 50–60 μg/kg has been reported to produce anesthesia with remarkable hemodynamic stability in patients with coronary artery disease (CAD). Because the authors had observed hypertension and tachycardia in response to noxious stimulation during aortocoronary bypass (ACB) operations in patients so anesthetized, they studied the hemodynamic changes and anesthetic conditions produced by fentanyl/O2/relaxant anesthesia in patients undergoing elective ACB. Twelve patients with left ventricular (LV) ejection fractions > 0.4 were maintained on propranolol until 10 hours before operation and were premedicated with fentanyl, diazepam, and scopolamine. Cannulae were inserted before the study commenced for measurement of intravascular pressures, arterial blood gases, and thermodilution cardiac output. The patients breathed 100 per cent oxygen throughout the study. Controlled ventilation aided by succinylcholine to reduce truncal rigidity maintained PaCO2 at 30–45 torr. Measurements were made after each of the following: breathing oxygen (control), 10 μ/kg fentanyl, 50 μg/kg fentanyl, and 0.1 mg/kg pancuronium, tracheal intubation, skin incision, and sternotomy. Fentanyl alone produced no significant hemo-dynamic changes. Fentanyl and pancuronium in combination produced increased heart rate and reduced stroke volume. Significant and progressively greater increases in mean arterial pressure and systemic vascular resistance followed intubation, skin incision, and sternotomy. Chest rigidity occurred in every patient at a lower fentanyl dose than did unresponsiveness. While fentanyl, 62.4 ± 2.9 μg/kg (SE), produced minor hemo-dynamic changes, it failed to block hemodynamic responses to noxious stimulation. Such changes resulted in increased cardiac work, and could have affected myocardial oxygen balance unfavorably. In eight of the 12 patients, following the last set of measurements, supplementary anesthetic agents were required to maintain hemodynamic stability during the surgical procedure. The authors suggest that this fentany1/102/relaxant technique should be modified for patients with severe CAD and reasonably good LV function.

The enflurane sparing effect of sufentanil in dogs.

There is a ceiling to the reduction of enflurane MAC by fentanyl in the dog. Sufentanil (SUF), a more potent narcotic, may be more efficacious in reducing enflurane MAC. To test this hypothesis, 25 mongrel dogs were studied in three groups. Group 1 (n = 8) received SUF in progressively increasing infusion rates from 0.005 μg · kg-1 · min-1 to a maximum of 1.215 μg · kg-1 · min-1. MAC was determined at stable SUF concentrations in plasma [SUF] during each infusion rate. Group 2 (n = 10) received SUF at a dose rate (0.007 μg · kg-1 · min-1) designed to produce approximately 35% MAC reduction, and MAC determinations were made at regular intervals over a mean infusion time of 7.6 ± 0.43 h (mean ± SEM). Group 3 (n = 7) received 1.215 μg · kg-1 · min-1 and were studied as in group 2 over an infusion time of 6.7 ± 0.42 h. In group 1, the highest infusion rate (1.215 μg · kg-1 · min-1) produced [SUF] = 48 ng/nil and reduced MAC by 71 ± 6%. This was not statistically different from the reduction which occurred at [SUF] = 0.92 ng/ml (57 ± 7%; infusion rate 0.015 μg · kg-1 · min-1; P = 0.21). In group 2, the degree of MAC reduction achieved by stable [SUF] (0.54 ± 0.08 ng/ml) declined over time (MAC reduction at start = 34 ± 2% versus 18 ± 4.0% at the end of the infusion; P = 0.001), suggesting the development of tolerance. In group 3 (1.215 μg · kg-1 · min-1), there was no statistically significant difference demonstrated between the degree of MAC reduction at the beginning versus the end of the infusion. The maximum reduction achieved by an infusion of 1.215 μg · kg-1 · min-1 (group 3) for nearly 7 h did not differ from that achieved with a series of progressively increasing infusion rates up to 1.215 μg · kg-1 · min-1 (group 1—70.5% reduction at [SUF] = 48 versus group 3—78% at 41 ng/ml). The authors conclude that there was a ceiling of approximately 70% reduction of enflurane MAC by SUF in the dog. This reduction was independent of the dose-rate at which it was achieved. At plasma concentrations below those producing a maximum reduction of MAC, acute tolerance was evident.

Tissue Redistribution of Fentanyl and Termination of Its Effects in Rats

The kinetics of fentanyl elimination from plasma suggest its rapid and extensive uptake by tissues. The authors determined the relationships between tissue and plasma concentrations of fentanyl. Six rats injected iv with 3H-fentanyl citrate (50 μg/kg) were sacrificed at each of the following times: 1.5, 5, 15, 30, 60, 120, and 240 min after injection. Tissues were analyzed for unchanged 3H-fentanyl citrate and for total 3H-radioactivity. Fentanyl effects were evident 10 s after injection; recovery began at 5 min and was complete within 60 min. Fentanyl concentrations in brain, heart, and lung equilibrated with that in plasma before 1.5 min and declined at the same rate (t1/2α = 8 min, t1/2β = 45 min). Fentanyl uptake by muscle and fat was slower and equilibration with plasma occurred by 120 min. Muscle accumulated 56 per cent of the dose within 5 min by which time brain fentanyl levels had declined by 90 per cent. Only 6 per cent of the dose was in fat at 5 min but this increased to a maximum of 17 per cent at 30 min. Fentanyl was extensively metabolized; metabolites represented 25 per cent of body 3H-radioactivity at 15 min, and 80 per cent at 4 h. The authors conclude that the short duration of fentanyl effect is due to its rapid redistribution from sites of action in the brain to sites of storage (muscle and fat) and biotransformation (liver). The elimination of fentanyl from the body is governed by its reuptake from storage sites and its metabolism in the liver. Most of the dose is ultimately excreted in the form of fentanyl metabolites in urine.